Pancreatic adenocarcinoma is the most lethal solid tumor challenging Americans today. Although 11th in prevalence, it ranks fifth in cancer mortality. Therefore, urgency is needed to understand the molecular mechanisms underlying the development of pancreatic cancer with the hope that this will lead to preventative and treatment strategies to improve the outcome of the disease. Although the underlying etiology and pathophysiology of pancreatic ductal cancer is poorly understood, there is an increasing body of published work, and preliminary data presented in this application suggesting that signaling pathways that control cell proliferation, differentiation, and apoptosis are dysregulated in pancreatic cancer. The mechanistic experiments outlined in this proposal are 100% relevant to pancreatic cancer and will test the central hypothesis that overexpression of GSK-3$ contributes to pancreatic cancer cell proliferation and survival and is thus a viable therapeutic target. We hypothesize that: (a) the GSK-3 gene is gained or amplified in a subset of patients with pancreatic cancer; (b) oncogenic K-Ras signaling regulates the expression of the GSK-3 promoter through its effects on Ets-1, Ets-2 and AP-1 transcription factors; (c) c-Src is a regulator of GSK-3 protein overexpression; (d) GSK-3 is required for the development of PDA in the LSL-KRasG12D mouse model of pancreatic cancer; (e) enzastaurin will inhibit GSK-3 function in vivo. In order to test these hypotheses we will (1) TO DETERMINE THE MECHANISM REGULATING THE EXPRESSION OF GSK-30 IN PANCREATIC ADENOCARCINOMA.; (2) DETERMINE THE REQUIREMENT FOR GSK-3 IN PANCREATIC CANCER PATHOGENESIS.; (3) PERFORM A PHASE II STUDY OF ENZASTAURIN AND GEMCITABINE IN UNTREATED, METASTATIC PANCREATIC CANCER PATIENTS WITH METASTASES AMENABLE TO BIOPSY. Together, the studies outlined in this proposal will provide invaluable information on the mechanisms regulating the expression of GSK-3 in pancreatic cancer, the role of GSK-3 in pancreatic cancer development and the effect of GSK-3 inhibition in the treatment of pancreatic cancer. Additionally, there is increasing evidence that GSK-3 participates in many human malignancies, thus, information obtained in the studies performed in this proposal might advance our understanding of this kinase in other human neoplasms.